1. Field of the Invention
This invention relates to a method for lowering plasma levels of lipoprotein known as lipoprotein(a) (Lp(a)) in animals comprising administering a compound which inhibits microsomal triglyceride transfer protein.
2. Summary of the Related Art
Heart disease remains one of the leading causes of death. The high incidence of heart disease has led to the identification of various risk factors that may be controlled in an effort to reduce such disease. One risk factor is hypercholesterolemia which is a condition of high blood levels of cholesterol. Cholesterol is a fatty substance that is made by the liver and also is present in many foods. Cholesterol circulates in th blood and is associated with several forms of lipoproteins. One such lipoprotein is known as low-density lipoprotein (LDL). LDL associates with cholesterol from the liver to form LDL-cholesterol (LCL-C), which takes cholesterol from the liver to cells throughout the body. High levels of LDL-C have been shown to cause rapid clogging of coronary arteries with fatty deposits, resulting in atherosclerosis, which often leads to heart attacks. Levels of LDL-C can be reduced, for example, by modifying diet to reduce fat and cholesterol intake and by daily exercise. In contrast, a second form of lipoprotein, high density lipoprotein (HDL), associates with cholesterol to lower circulating levels of cholesterol by removing it from cells and recycling it to the liver for disposal.
A modified form of LDL is known as lipoprotein(a) (Lp(a)). Lp(a) consists of LDL covalently linked to apolipoprotein(a), (apo(a)) via a disulfide bond. Elevated levels of Lp(a) are associated with the development of atherosclerosis, coronary heart disease, myocardial infarction, cerebral infarction, and restenosis following balloon angioplasty. In fact, increased Lp(a) levels appear to be an excellent predictor for stroke. Accordingly, high concentrations of Lp(a) is one of the major risk factors leading to death from heart disease.
Wetterau et al. (U.S. Pat. No. 5,595,872) describe compounds that inhibit the protein known as microsomal triglyceride transfer protein (MTP) and have the structural formula: ##STR2## wherein R.sup.1 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkyl, or cycloalkylalkyl, each of which is optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from halo, alkyl, alkenyl, alkoxy, aryloxy, aryl, arylalkyl, alkylmercapto, arylmercapto, cycloalkyl, cycloalkylalkyl, heteroaryl, and heteroarylalkyl. Examples of oxo-substituted groups are described in Cortizo, L., J. Med. Chem. 34: 2242-2247 (1991). In vitro, MTP catalyzes the transport of lipid molecules between phospholipid membranes. Wetterau & Zilversmit, Chem, Phys. Lipids 38, 205-22 (1985). The physiological role of MTP has not been demonstrated. Presumably, it plays a similar role in vivo, and thus plays some role in lipid metabolism. The subcellular (lumen of the microsomal fraction) and tissue distribution (liver and intstine) of MTP have led to speculation that it plays a role in the assembly of plasma lipoproteins, as these are the sites of plasma lipoprotein assembly. Wetterau & Zilversmit, Biochem, Biophys. Acta, 875: 610-7 (1986). Wetterau et al. determined that these MTP inhibiting compounds could decrease the MTP-catalyzed transfer of triglyceride (TG), cholesteryl ester (CE), and phosphatidylcholine (PC) between small unilamellar vesicles (SUV). Presently, however, there are no reports that the above reference compound are effective in decreasing the plasma levels of Lp(a). We have now discovered that plasma Lp(a) can be lowered by administering compounds of formula I, and accordingly an object of this invention is to provide a method for lowering Lp(a), and thereby treating and preventing coronary artery disease.